多维替尼(TKI258，CHIR-258)是一种针对FLT3、KIT、FGFR、VEGFR、PDGFRα和PDGFRβ的多靶点受体酪氨酸激酶抑制剂，其IC50分别为1纳米、2纳米、8-9纳米、8-13纳米、210纳米和27纳米[1]。

     TKI258以150 nM或90 nM的IC50值特异性抑制ZNF198-FGFR1或BCR-FGFR1细胞的生存力。TKI258以剂量依赖性方式抑制ERK和STAT5基因的磷酸化。TKI258还特异性抑制FGFR1OP2-FGFR1阳性KG1和KG1A细胞系的增殖和存活，增加凋亡水平[2]。在肝细胞癌(HCC)细胞中，TKI258和替加珠单抗的组合恢复了HCC细胞对TRAIL和替加珠单抗诱导的凋亡的敏感性。TKI258抑制STAT3的磷酸化，并随后降低Mcl-1、生存素和Cylcin D1的蛋白水平。TRAIL和TKI258的联合治疗增加了SHP-1的活性[3]。用TKI258抑制FGFR3降低了waldenstr m巨球蛋白血症(WM)细胞存活率，增加了细胞凋亡，并诱导细胞周期停滞。TKI258减少WM与骨髓细胞的相互作用，逆转其增殖。TKI258与其他药物具有叠加效应[4]。

在体内，替加珠单抗和TKI258的组合抑制了Huh-7异种移植肿瘤的生长[3]。TKI258减少了WM肿瘤的进展[4]。

产品性质：

Cas No.:405169-16-6

别名:多韦替尼; CHIR-258; TKI258

化学名: (3Z)-4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1,3-dihydrobenzimidazol-2-ylidene]quinolin-2-one

Canonical SMILES:CN1CCN(CC1)C2=CC3=C(C=C2)NC(=C4C(=C5C(=NC4=O)C=CC=C5F)N)N3

分子式:C21H21FN6O

分子量:392.43

溶解度:≥ 36.35mg/mL in DMSO

储存条件:Store at -20°C

注意事项：

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References:

[1].  Trudel S, Li ZH, Wei E, Wiesmann M, Chang H, Chen C, Reece D, Heise C, Stewart AK. CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood. 2005 Apr 1;105(7):2941-8.

[2].  Chase A, Grand FH, Cross NC. Activity of TKI258 against primary cells and cell lines with FGFR1 fusion genes associated with the 8p11 myeloproliferative syndrome. Blood. 2007 Nov 15;110(10):3729-34.

[3].  Chen KF, Chen HL, Liu CY, Tai WT, Ichikawa K, Chen PJ, Cheng AL. Dovitinib sensitizes hepatocellular carcinoma cells to TRAIL and tigatuzumab, a novel anti-DR5 antibody, through SHP-1-dependent inhibition of STAT3. Biochem Pharmacol. 2012 Mar 15;83(6):769-77.

[4].  Azab AK, Azab F, Quang P, Maiso P, Sacco A, Ngo HT, Liu Y, Zhang Y, Morgan BL, Roccaro AM, Ghobrial IM. FGFR3 is overexpressed waldenstrom macroglobulinemia and its inhibition by Dovitinib induces apoptosis and overcomes stroma-induced proliferation. Clin Cancer Res. 2011 Jul 1;17(13):4389-99.